C-21 lower alkylsulfinyl esters of certain 21-hydroxycorticosteroids

ABSTRACT

C-21 Lower alkylsulfinyl esters of certain 21hydroxycorticosteroids are good antiinflammatory agents which have both topical and systemic activities. These compounds are best prepared by a 2-step process which involves the esterification of a 21-hydroxycorticosteroid with a lower alkylsulfide-acid and oxidation of the resulting sulfide ester with a mild oxidizing agent to the corresponding sulfinyl ester.

Elnited States Patent Scribner 1 June 27, 1,972

C-21 LOWER ALKYLSULFINYL ESTERS OF CERTAIN 21- HYDROXYCORTICOSTEROIDSInventor: Richard M. Scribner, Wilmington, Del.

Assignee: E. I. du Pont de Nemours and Company,

Wilmington, Del.

Filed: April 22, 1970 Appl. No.2 31,003

US. Cl ..260/239.55, 260/2395, 260/397.45,

- 195/51 Int. Cl C07c 1 69/32 Field of Search ..-.260/397.45;

Machine Searched Steroids Primary Examiner-Elbert L. Roberts 7 IA!!0rncy.lumcs H. Ryan [57 ABSTRACT 9 Claims, No Drawings C -21 LOWERALKYLSULFINYL ESTERS OF CERTAIN 2 I-HYDROXYCORTICOSTEROIDS BACKGROUND OFTHE INVENTION 1. Field of the Invention This invention is directed tolower alkylsulfinyl esters of certain 2 1 -hydroxycorticos teroids.

2. Prior Art Many natural or synthetic corticosteroids have valuableantiinflammatory properties and are useful as topical and systemicantiinflammatory agents. However, it is generally recognized that a needexists for antiinflammatory agents which show yet greater efficacyand/or diminished side effects.

The potent skin-penetrating properties of dimethyl sulfoxide (DMSO) havebeen recognized during the past few years, and this substance has beenused experimentally as a solvent to enhance skin penetration of a numberof biologically active materials. The great penetration of DMSO throughthe skin is probably related to the dipolar character of the sulfoxidegroup and its hydrophilic character. DMSO, however, is not a practicalsolvent for drugs because it sometimes has undesirable side effects andcauses skin irritation when applied in large amounts. Chemicalmodification of a biologically active material by increasing its polarcharacter and/or hydrophilic properties would appear to offer a goodpossibility of improving its penetration through the skin orgastrointestinal tract while at the same time favorably altering itsdistribution between the aqueous and liquid phases of the body. However,this approach often fails because the chemical modification alters thebiological properties of the material and makes it unsuitable for theintended use.

There have been in the past no reported attempts either to increase thepenetration, potency, or duration of activity or to reduce the sideeffects of corticosteroid compounds useful as antiinflammatory agents byexterifying a steroid alcohol with an alkylsulfinylcarboxylic acid.

SUMMARY OF THE INVENTION According to this invention, it has now beendiscovered that lower alkylsulfinyl esters of certain2l-hydroxycorticosteroids have good antiinflammatory activity and aresuitable for both topical and systemic use.

Although the term "corticosteroid is well known to the art, it has beenvariously used to designate the origin, the chemical structure, or thebiological activity of certain steroids. The compounds contemplated bythe present invention are C-2l esters of 21-hydroxy-20-ketopregnanederivatives which have the characteristic A -3-keto structure andpreferably an oxygenated functional group at C-1 1. Other substituents,especially lower alkyl, hydroxyl, and halogen, can be present, as shownbelow.

The compounds of the present invention can be represented by thefollowing Formula 1, in which the methyl groups at C-lO and C-13 areindicated by vertical lines.

in which a is a single bond or a double bond; R is hydrogen or methyl; Ris hydrogen, chlorine, or fluorine; R is oxygen, one a-hydrogen and oneB-hydroxyl, or one a-hydrogen and one B-chlorinc; R is two hydrogens,one hydrogen and one methyl, one hydrogen and one hydroxyl, one hydrogenand one acetoxyl, or methylene; R is hydroxyl; R and R together can formthe group in which each of R and R' can independently be an alkyl of Thenew esters of the present invention are most conveniently prepared by a2-step process involving the esterification of the C-21 hydroxyl withthe appropriate sulfide-acid, followed by mild oxidation of the sulfideto the sulfoxide.

DETAILED DESCRIPTION OF THE INVENTION Representative starting2l-hydroxycorticosteroids which can be converted to their2l-alkylsulf1nyl esters include those listed in Table I, below.

TABLE I l711,21-dihydroxy-4-pregnene-3,1 1,20-trione (cortisone);

1 18,1 711,2 l-trihydroxy-4-pregnene-3,20-dione (cortisol); 2l-hydroxy-4-pregnene-3,l 1,20-trione;

911-fluoro- 1 711,2 1 -dihydroxy 4-pregnene-3 ,1 1,20-trione;901-fluoro- 1 1B, 1 711,2 l-trihydroxy-4-pregnene-3 ,20-dione;911-fluoro-1701,21-dihydroxy-l ,4-pregnadiene-3,l 1,20-trione;901-fluoro-l 1B,]711,21-trihydroxy-l,4-pregnadiene-3 ,20- dione;

911-f1uoro-1611-methyl-l 13,1711,21-trihydroxy-4-pregnene- 3,20-dione;

911-fluorol 611-methyl-1 1B,l711,2l-trihydroxy-l,4-pregnadiene-3,20-dione;

911-fluoro-l 601-methyll 711,2'1-dihydroxy-1 ,4-pregnadiene- 3,11,20-trione;

901-fluorol 611-methyl-1 1,8, 1 711,2 l-trihydroxy-l ,4-pregnadiene-3,20-dione;

911-fluoro-601-methyl1 1/3,1701,2ltrihydroxy-1 ,4-pregnadiene-3,20-dione;

911-fluoro-601-methyl-l 113,1711,2l-trihydroxy-4pregnene- 3,20-dione;

6a-methyl- 1 711,2 l-dihydroxy-4-pregnene-3,1 l ,ZO-trione; 611-methyl-l1B, 1 711,2 1 -trihydroxy- 1 ,4-pregnadiene-3,20- dione;

l 18,1611, 1 711,2 l-tetrahydroxy-l ,4-pregnadiene-3 ,20-dione; l1B,l611,1711,2l-tetrahydroxy-l,4-pregnadiene-3,20-dione 16,17-acetonide;

9a-fluoro-l 1B, 1 611, l711,21-tetrahydroxy-1 ,4-pregnadiene-3,20-dione;

911-fluoro-1 1B,l711,l711,21-tetrahydroxy-l ,4-pregnadiene- 3 ,ZO-dione16,17-acetonide;

911-fluoro-l 1,3,1611,l711,21 tetrahydroxy-l ,4-pregnadiene- 3,20-dione16,17-phenylacetonide;

911-fluoro-l 13,1611,l711,2l-tetrahydroxy-l ,4-pregnadiene- 3,20-di0ne16,17-cyclohexanonide;

911,1 1 B-dichloro- 1 711,2 1 -dihydroxy-4-pregnene-3 ,20-dione 9a, 1lB-dichloro- 1 701,2 l-dihydroxyl ,4-pregnadiene-3,20- dione;

2 l -hydroxyl 7a-acetoxy-l ,4-pregnadiene-3 ,l 1,20-trione; 1 15,2 1-dihydroxy-l 7a-acetoxy-4-pregnene-3 ,ZO-dione; 9a-fluoro-2 1 -hydroxyl7a-acetoxy 4-pregnene-3,l l ,20- trione; and

pregnene-3,20-dione.

Most of the above and similar starting materials are known, and many arecommercially available.

Other corticosteroids which have not been previously reported or are notreadily available can be made by methods known to skilled chemistshaving understanding of steroid reactions. Virtually all of thecorticosteroid compounds comprised within the scope of the presentinvention can be made by several alternative routes. The choice willdepend on the I starting materials available as well as on the overalleconomics. Certain syntheses can involve the use of both chemical andmicrobiological techniques. Thus, the llahydroxy group often can beintroduced through a technique using the microorganism Curvularialunata.

While Table I shows some possible corticosteroidsin the form of their16,17-acetonide, phenylacetonide, or cyclohexanonide derivatives, otherketal derivatives also can be used. In these compounds, each of R and Rcan be any one of the following representative radicals: methyl, ethyl,propyl, isopropyl, butyl, pentyl, hexyl, cyclopentyl, cyclohexyl, orphenyl; and R together with R can be tetramethylene or pentamethylene.Such ketals are readily obtained from the l6a,l7B-dihydroxysleroids andappropriate ketones in the presence of an acid catalyst, such asperchloric acid.

The alkylsulfinyl acid portion of the corticosteroid ester can have avariety of possible structures. The divalent hydrocarbon radical,designated as X in Formula 1, can be alkylene, arylene, alkarylene, oraralkylene. Suitable X hydrocarbon radicals include those listed inTable ll.

TABLE II methylene ethylene l,3-propylene 1,2-propylene l,4-butylene2,3-butylene l,2-butylene 2-methyll ,2-propylene l,5-pcntylene2,2-dimcthyll ,3-propylene l,6-hexylene 2,2-dimethyll ,4-butylenel,7-heptylene l, l O-decylene 2,2,4,4-tetramethylhexylene p-phenyleneo-phenylene m-phenylene 1 ,4-naphthylene 1,8-naphthylene a,4-tolylenea,3-tolylene and 4-ethyl-2,5-tolylene The lower alkyl radical,designated as R in Formula 1, can be methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl or t-butyl. As mentioned earlier, R and X canbe joined together to form cyclic structures, some of which are shownbelow:

Lower alkylsulfinyl acids can be readily prepared by oxidation of thecorresponding sulfide-acids with a mild oxidizing agent, such as anorganic peroxyacid or hydrogen peroxide. The reaction sometimes alsogives varying amounts of .sulfones, which are undesirable by-products.The sulfones can be removed by several techniques, including thin layeror column chromatography, distillation, crystallization, or filtration.

It has been found, however, that esterification of a 21-hydroxycorticosteroid with either a free alkylsulfinyl acid or analkylsulfinyl acid chloride is impractical and results at best in lowyields of the desired products. Pummerer rearrangement is one of theimportant side reactions. The preferred process for the preparation ofthe novel esters of the present invention is the esterification of a2l-hydroxycorticosteroid with a sulfide-acid, followed by the oxidationof the sulfide to the sulfoxide.

Many starting sulfide-acids are readily available, but all of them canbe made by conventional reactions. A simple way to make a sulfide acidinvolves a reaction of the sodium salt of a halogen acid with amercaptan in alkaline medium. This and other synthetic techniques aredescribed in Chapter 3 of Organic Sulfur Chemistry Vol. III, by E.E..Reid (Chemical Publishing Co., New York, 1960).

Known sulfide-acids include the following representative compounds,tabulated below. They have the formula um, s (M Table Ill-Continued andCOOH

Other sulfide-acids can be prepared by the conventional syntheticmethods of organic chemistry. For example, 1,5-dihydroxypentane-3-carboxylic acid, which can be prepared in severalsteps from diethyl malonate and ethylene oxide, can be converted tol,5-dibromopentane-3-carboxylic acid (e.g., by treatment withtn'phenylphosphine dibromide and then water); this compound on treatmentwith sodium sulfide gives 4-thiacyclohexane-l-carboxylic acid.Thiacyclopentanecarboxylic acids can be prepared by chemical reductionor palladium catalyzed hydrogenation of the correspondingthiophenecarboxylic acids.

The first step of the process, the esterification with a sulfideacid, ismost conveniently accomplished by contacting under controlled conditionsa sulfide-acid chloride with a 2 l-hydroxycorticosteroid. The l7whydroxyand the llfi-hydroxy groups are less reactive than the 2 l-hydroxy groupand usually do not require protection. The reaction can be carried outunder nitrogen at a temperature of about -30 to +30 C. in an inertsolvent, such as a chlorinated hydrocarbon, or an ether. Suitablesolvents include chloroform, tetrahydrofuran, or dioxane. Usually, aproton acceptor also is present in the solution. This generally is atertiary amine, such as pyridine, triethylamine, trimethylamine,N,N-dimethylaniline, and N- methylmorpholine. Preferably, the amineitself, especially pyridine, serves as the reaction solvent and is,therefore, used in a large excess. The sulfide-acid chloride, on theother hand, preferably is used in about a stoichiometric proportion.

The acid chloride is added gradually either neat or in a solution in thesame or a different inert solvent with good stirring. After addition ofthe acid chloride the solution is stirred for an additional period of afew hours to several days. The sulfideacid ester is recovered by anyconventional technique, such as, for example, extraction with anappropriate solvent after dilution of the reaction mixture with water.The crude ester can be purified by chromatography and/orrecrystallization.

instead of the acid chloride, the appropriate sulfide-acid anhydride ormixed anhydride can be used. The reaction usually is carried out at atemperature of about 30 to +30 C. Tertiary amines, such as pyridine,catalyze the reaction, which can also be carried out in pyridinesolution. These esters can also be prepared by reaction of salts ofsulfide-acids with corticoid 2 l -sulfonate esters.

The sulfide-acid ester formed in the first step is oxidized to thecorresponding alkylsulfinyl ester by contacting the former with a mildoxidant, such as a peroxy compound, oxides of nitrogen, sodium bromate,or a periodate. Hydrogen peroxide can be used in this step, or moreconveniently a peroxyacid, including perbenzoic acid, peracetic acid, orm-chloroperbenzoic acid.

In order to minimize the possibility of the formation of undesirableby-products, such as sulfoxides, the oxidation step is carried out at alow temperature, preferably within the range of 20 to 25 C., and astoichiometric amount of the peroxy compound is used. Neighboring 16aand17a-hydroxy groups can be protected by the formation of an acetonide,which can later be split in a weakly acid medium if desired.

While a large number of lower alkylsulfmyl esters of 21-hydroxycorticosteroids can be made, the 2,2-dimethyl-3-methylsulfinylpropionate esters appear to offer a particularlywell-balanced combination of steric hindrance toward hydrolysis and oflipophilic and hydrophilic properties. Since neither the starting2,2-dimethyl-3methylthiopropionyl chloride nor its precursor,2,2-dimethyl-3-methylthiopropionic acid have been heretofore reported,their preparation is described below, in Example A. Temperatures are indegrees centigrade,

(a) Methylmercaptan, 30 g. (0.60 mole), is bubbled into a cold solutionof 27 g. (0.50 mole) of sodium methoxide in ml. of dry methanol. To thissolution cooled in an ice bath is then added 50 g. (0.50 mole) ofpivalolactone dropwise at a rate adjusted to keep the temperature of thereaction mixture at about 15. After stirring for 1 hour at roomtemperature,

the reaction mixture is diluted with about 300 ml. of ether and thenpoured into 500 ml. of ice water. The ether layer is drawn off in aseparating funnel, and the aqueous layer is extracted a second time withfresh ether. The aqueous layer is then acidified with 45 ml. of conc.HCl, extracted with ether twice, and this ether extract is washed withwater once, dried over Na SO and evaporated in vacuo, to give a liquidwhich is distilled through an 18-inch spinning band column. Thedistillation gives 45 g. (62 percent yield) of pure 2,2-dimethyl-3-methylthiopropionic acid, b.p. 79/0.2 mm.

Anal. Calcd. for C,,H,,SO,:

Found:

nmr (CDCl TMSi), Hz at 60 MHz: 743 (s, 1, CO2H); S, 2, SCH2); 128 (s, 3,CH3S-), 77 [8, 6, c cH, IR (CHClQ); 3.34, 3.42 (C-H), 3-4 [1. 00 11 5.85con-i 7.21, 7.32 [C(CH3)2].

(b) A solution of 3-methylthio-2,2-dimethylpropionic acid in benzene istreated with excess thionyl chloride and 1 drop of dimethylformamide.After 30 min. the reaction mixture is heated at reflux temperature for 1hr. and distilled to give 3- methyl-2,2-dimethylpropionyl chloride, b.p.about 35/0.2 mm.

The invention is now illustrated by representative examples of certainpreferred embodiments thereof. All temperatures are in degreescentigrade.

PREFERRED EMBODIMENTS EXAMPLE 1 l13,17a,2l-Trihydroxy-l,4-pregnadiene-3,20-dione 21-(2',2-dimethyl-3'-methylsulfinylpr0pionate) a. To a solution of 2.3 g. (64mmoles) of 11B,l7a,2ltrihydroxy-l,4-pregnadiene-3,20-dione in 25 ml. ofpyridine under nitrogen and cooled in an ice bath is added 1.2 g. (72mmoles) of 2,2-dimethyl-3-methylthiopropionyl chloride from Example A.The reaction mixture is stirred with continued cooling for 1 hr. and atroom temperature overnight. It

is then poured into water, extracted into ethyl acetate and methylenechloride, washed with percent aqueous HCl, and dried over Na SOEvaporation of the organic solvent and crystallization of the residuegives pure 1 1B, 1 701,2 l-trihydroxyl ,4-pregnadiene-3 ,20-dione 2 l 2,20-dimethyl-3 methylthiopropionate), m.p. l96l 97(from ethanol).

Anal. Calcd. for C H SO 6. Found: 6.

A (EtOH) 243 mp. (13,900), A (KBr) 2.90-2.95 (OH), 3.36, 3.42, 3.47(CH), 5.77 (ester C O), 5.83 (CO), 6.05 (conj. C O), 6.20-6.26 (conjCC)p..

b. A solution of 1.627 g. (3.32 mmol'es) of the methylthioester in 650ml. of methylene chloride is cooled in an ice-salt mixture and stirredwhile a solution of 0.676 g. (3.32 mmoles, 85 percent assay) m- Anal.Calcd. for C,-,H:,,,SO,:

C, 63. Found: C, 64. S, 6.28;

[01],, 80, c 1.03 pyridine; A (EtOH) 243 (15,100), A (KBr) 2.90 (OH),3.32, 3.38, 3.44 (C-H), 5.79 and sh (ester and C21 C O), 6.17 and 6.22sh (C C), 9.87 p (S--O); H nmr (d pyridine-TMSi) Hz at 60 MHz: 80 (s, 3,C l 8 CH 93 (s, 3, Cl9 CH 97 [s, 6, C(CH 156 (3, CH SO), 189 (2, SOCH284 (2, C-2l CH mass spec. (70 ev) calcd: 506.2336, found: 506.2356.

' EXAMPLE 2 1 1B 1 701,2 1 -Trihydroxyl ,4-pregnadiene-3 ,20-dione 2 l-(pmethylsulfinylbenzoate) HO H (Formula 1: a is a double bond; R =R =H; RR4: H H

It 0H; X is the p-phenylene radical; R=CHa) o l 6 ll CH2O K -so11 5:0

a. By a procedure analogous to Example 1, part (a'),.

1 1B,] 7a,21-trihydroxy-l ,4-pregnadiene-3,20-dione is treated withp-methylthiobenzoyl chloride, giving the corb. By a procedure analogousto Example 1, part (b), this ester is oxidized tollB,l7a,2l-trihydroxy-l,4-- prcgnadiene-J,ZO-dione 2l-(p-methylsulfinylbenzoate), m.p. 255258 (from ethanol). Anal.

Calcd. for C H SC C, 66.05; H, 6.48; S, 6.08; Found: C, 66.08;H, 6.77;8,5.86.

EXAMPLE 3 1 1B, 1 711,2 l-Trihydroxyl ,4-pregnadiene-3,20-dionemethylsulfinylpropionate) no (Formula 1: a is a double bond; R =R =H; Rx; R

a. By a procedure analogous to Example 1, part (a) 18.0 g. ofl1B,l7a,2l-trihydroxy-l,4-pregnadiene-3,20-dione in m1. of pyridine, istreated with 8.4 g. of 3- methylthiopropionyl chloride, giving thecorresponding ester.

b. By a procedure analogous to Example 1, part (b) the thioester isoxidized to ll,B,l7a,2l-trihydroxy-1,4- pregnadiene-3 ,20-dione 21 (3'-methylsulfinylpropionate).

In like manner, any 2l-hydroxycorticosteroid of Table 1, above, can becontacted with an acid chloride or anhydride prepared from anysulfide-acid of Table III or from a cyclic sulfide-acid, such as4-thiacyclohexane-l-carboxylic acid, 3- thiacyclopentane-l-carboxylicacid, 2-(4-thiacyclohexyl)- acetic acid, and 2-(3-thiacyclopentyl)acetic acid, to give the corresponding C-2lsulfide-acid ester. Each such ester can be contacted with one equivalentof a mild oxidant to give the corresponding C-2 1 alkylsulfinyl ester.

The esters of this invention possess useful antiinflammatory activitywhen administered orally, topically, or by injection. For example, thesulfoxide ester of Example I-b is a potent inhibitor ofcarageenin-induced rat-paw edema when administered orally.Significantly, this sulfoxide ester is much more active than thecorresponding sulfide ester of Example I- a. The biological differencesbetween these closely related structures arise from the unusualproperties of the sulfoxide linkage in the former ester. Furthermore,the sulfoxide ester of Example l-b displays superior oral activity andfewer side effects than the corresponding 2l-hydroxy steroid,prednisolone. This is consistent'with the concept of enhanced absorptionof the sulfoxide ester in the gastrointestinal tract.

Thus, prednisoloneand the esters of Example I were administered orallyas solutions to groups of 6 male rats. One hour after dosing, 0.05 ml.of 1 percent carrageenin solution was injected into the plantar regionof the right hind paw of each rat. Foot volume was measured bydisplacement of mercury immediately after injection and again 3 hourslater, the difference being the volume of induced edema. Urine sampleswere collected during the 4-hour period following dosing. The followingsummary of data from these experiments, presented in Table IV belowshows that orally administered sulfoxide ester (Example l-b) is morepotent than either the corresponding sulfide ester (Example l-a) orprednisolone with respect to edema inhibition. Furthermore, consistentwith its hydrophilic character, the sulfoxide ester shows lessundesirable effect on electrolyte excretion than does prednisolone.

TABLE IV Dose (mg/kg.) Edema to Increase Na Inhibition Excretion 2-FoldED mg./kg. Over Control Prednisolone 3.5 4.7 Sulfide Ester 16 Examplel-a Sulfoxide Ester 0.94 10 Example l-b C-2l Lower alkylsulfinyl estersof 2l-hydroxycorticosteroids are useful as orally, parenterally, ortopically applied antiinflammatory agents. They can be administeredorally as pills, tablets, or powders (free or encapsulated), or asliquids in the form of solutions, suspensions, or syrups. Topically theesters can e administered as creams, ointments, solutions, suspensions,foams, aerosols, or powders, or from coatings on films or tapes, mixedif desired with a pharmaceutically acceptable inert vehicle orcombinations of inert vehicles. Parenterally they can be injected assuspensions or solutions in pharmaceutically acceptable oils or aqueousmedia. Orally, topically, or parenterally the novel esters of thisinvention can be administered alone or in combination withpharmaceutically active agents, such as antibiotics or analgesics.

The embodiments of the invention in which an exclusive property orprivilege is claimed are defined as follows:

1. An ester having antiinflarnmatory activity and represented by theformula in which a is either a single or a double bond; R is hydrogen ormethyl; R is hydrogen, chlorine, or fluorine; R is oxygen, onea-hydrogen and one B-hydroxyl, or one ahydrogen and one B-chlorine; R ishydrogen, one hydrogen and one methyl, one hydrogen and one hydroxyl,one hydrogen and one acetoxyl, or

group in which each of R and R is methyl.

3. 1 1B,17a,2l-Trihydroxy-l ,4-pregnadiene-3,20-dione 21-(2,2-dimethyl-3-methylsulfinylpropionate), the compound of claim 1 inwhich a is a double bond; R and R are hydrogen atoms; R is one hydroxyland one hydrogen; R is two hydrogen atoms; R is hydroxyl; X is the2-methyll ,2- propylene radical; and R is methyl.

4. 1 l,B,l7a,2l-Trihydroxy-l ,4-pregnadiene-3,20-dione 21-(p-methylsulfinylbenzoate), the compound of claim 1 in which a is adouble bond; R and R are hydrogen atoms; R is one hydroxyl and onehydrogen; R is two hydrogen atoms; R is hydroxyl; X is the p-phenyleneradical; and R is methyl.

5. l 1B,17a,2l-Trihydroxy-1,4-pregnadiene-3 ,20-dione' 2 l-(3-methylsulfin lpropionate), the com ound of claim 1 in which a is adou le bond; R and R are ydrogen atoms; R is one hydroxyl and onehydrogen; R is two hydrogen atoms; R" is hydroxyl; X is the 1,2-ethyleneradical; and R is methyl.

6. A process for preparing an ester of claim 1 consisting in:

a. contacting a 21-hydroxy-20-ketopregnane with a chloride or anhydrideof a sulfide-acid of the formula 0 HO-ii-XS R wherein X and R are asdefined in claim 1 at a temperature of about -30 to +30 C. to produce aC-21 sulfide-acid ester; and

b. oxidizing the said C-2l sulfide-acid ester by contacting it at atemperature of 20 to 25 C. with a mild oxidant of the group: oxides ofnitrogen, hydrogen peroxide, a carboxylic peroxy acid, sodium bromateand sodium periodate.

7. The process of claim 6 in which step (a) is carried out with asulfide-acid chloride in the presence of a tertiary amine at atemperature of about 30 to +10 C.

8. The process of claim 7 in which the tertiary amine is pyridine.

9. The process of claim 7 in which the step (b) is carried out withm-chloroperbenzoic acid as the oxidizing agent.

2. A steroid of claim 1, in which R4 and R5 together form the group inwhich each of R6 and R7 is methyl.
 3. 11 Beta ,17 Alpha,21-Trihydroxy-1,4-pregnadiene-3,20-dione21-(2'',2''-dimethyl-3''-methylsulfinylpropionate), the compound ofclaim 1 in which a is a double bond; R1 and R2 are hydrogen atoms; R3 isone hydroxyl and one hydrogen; R4 is two hydrogen atoms; R5 is hydroxyl;X is the 2-methyl-1,2-propylene radical; and R is methyl.
 4. 11 Beta ,17Alpha ,21-Trihydroxy-1,4-pregnadiene-3,20-dione21-(p-methylsulfinylbenzoate), the compound of claim 1 in which a is adouble bond; R1 and R2 are hydrogen atoms; R3 is one hydroxyl and onehydrogen; R4 is two hydrogen atoms; R5 is hydroxyl; X is the p-phenyleneradical; and R is methyl.
 5. 11 Beta ,17 Alpha,21-Trihydroxy-1,4-pregnadiene-3,20-dione21-(3''-methylsulfinylpropionate), the compound of claim 1 in which a isa double bond; R1 and R2 are hydrogen atoms; R3 is one hydroxyl and onehydrogen; R4 is two hydrogen atoms; R5 is hydroxyl; X is the1,2-ethylene radical; and R is methyl.
 6. A process for preparing anester of claim 1 consisting in: a. contacting a21-hydroxy-20-ketopregnane with a chloride or anhydride of asulfide-acid of the formula wherein X and R are as defined in claim 1 ata temperature of about -30 to +30* C. to produce a C-21 sulfide-acidester; and b. oxidizing the said C-21 sulfide-acid ester by contactingit at a temperature of -20* to 25* C. with a mild oxidant of the group:oxides of nitrogen, hydrogen peroxide, a carboxylic peroxy acid, sodiumbromate and sodium periodate.
 7. The process of claim 6 in which step(a) is carried out with a sulfide-acid chloride in the presence of atertiary amine at a temperature of about -30* to +10* C.
 8. The processof claim 7 in which the tertiary amine is pyridine.
 9. The process ofclaim 7 in which the step (b) is carried out with m-chloroperbenzoicacid as the oxidizing agent.